Biomedicine & Pharmacotherapy 112 (2019) 108615

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets T

and treatment strategies to pace wound healing
Satish Patel, Shikha Srivastava, Manju Rawat Singh, Deependra Singh
⁎

University Institute of Pharmacy, Pt. Ravishankar Shukla University, 492010, Raipur, C.G., India

ARTICLE INFO ABSTRACT

Keywords: Wound management in diabetic patient is of an extreme clinical and social concern. The delayed and impaired
Diabetes healing makes it more critical for research focus. The research on impaired healing process is proceeding hastily
Diabetic wounds evident by new therapeutic approaches other than conventional such as single growth factor, dual growth factor,
Wound healing skin substitutes, cytokine stimulators, cytokine inhibitors, matrix metalloproteinase inhibitors, gene and stem
Growth factor
cell therapy, extracellular matrix and angiogenesis stimulators. Although numerous studies are available that
Compromised wounds
Diabetic foot ulcer
support delayed wound healing in diabetes but detailed mechanistic insight including factors involved and their
role still needs to be revealed. This review mainly focuses on the molecular cascades of cytokines (with growth
factors) and erstwhile factors responsible for delayed wound healing, molecular targets and recent advancements
in complete healing and its cure. Present article briefed recent pioneering information on possible molecular
targets and treatment strategies including clinical trials to clinicians and researchers working in similar area.

1. Introduction alteration in normal physiological functions like deprived blood circu-

Diabetes is a multifaceted metabolic disease that affects more than 340
million individuals and about 20% of them develop diabetic wounds
worldwide [1]. Leg or foot ulcers are most common wounds in diabetic
patients. Diabetic patients have declined ability to metabolize glucose
resulting in hyperglycaemic conditions which further complicate the
wound healing process. This can result in stalled chronic wounds. The
incidence of delayed healing process in diabetic patient is increasing
globally due to lack of preventive and control measures. About 2.5%–15%
of yearly world-wide health budgets are consumed on diabetes mellitus
and diabetic wounds stake a major part. WHO report speculate that dia-
betes will be the 7th foremost reason for death in 2030. In 2014, 9% of
adults had diabetes and was the reason for death of 1.5 million patients in
2012. More than 80% of diabetes deaths occur in low- and middle-income
countries [1,2]. Approximately 50%–70% of all the limb amputations are
because of diabetic wounds and it was reported that in every 30 s, one leg
is amputated due to diabetic wounds in worldwide [3].
Wound healing is a multifaceted and dynamic process which results
in the restoration of anatomic integrity with analogous function. Prime
requirement for wound management is rapid and complete healing
without spreading infection and sepsis. Acute wounds generally heal
with ease without any issue. The major concern involves age related
lation, obesity, diseases like diabetes and stressed environmental con-
ditions. Based on their healing potential wounds are indicated into two
forms i.e. chronic and acute one. Chronic wounds include tissue injuries
which do not heal in an organized set of stages and takes more than 12
weeks for healing [4,5]. Normally, healing process starts with hae-
mostasis that checks the blood loss and invasion of microbes to
wounded area. This phase is rapidly followed and overlapped by an
inflammatory phase, in which pro-inflammatory cells neutrophils up-
regulate (initially) followed by macrophages which clean up debris and
pathogens along with growth factors and other cytokines and cells.
Proliferative phase overlaps inflammatory phase in which new tissue,
new blood vessels (angiogenesis) and matrix construction is initiated to
fill the wounded area. The final remodelling phase then increases the
tensile strength of the extracellular matrix and reduces the blood supply
to the damaged area [6–9].
DWs1 are one of the major concerns which mainly includes leg
ulcer/diabetic ulcer. Diabetes delay healing process because it impairs
each phase of wound healing i.e. haemostasis, inflammation, pro-
liferation and remodelling phase, which has a long-term negative effect
on quality of life, morbidity and mortality (Fig. 1). DWs are char-
acterized by delayed acute wounds and chronic wounds unveiling im-
paired healing due to a postponed, incomplete, or uncoordinated

⁎
Corresponding author.
E-mail address: deependraiop@gmail.com (D. Singh).
1
Diabetic Wounds

https://doi.org/10.1016/j.biopha.2019.108615
Received 17 October 2018; Received in revised form 19 January 2019; Accepted 23 January 2019
0753-3322/ © 2019 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
S. Patel, et al.
Fig. 1. Interruption of normal wound healing process in diabetes.
healing process. DWs exhibit a persistent inflammatory phase asso-
ciated with an impediment in the formation of mature granulation
tissue and reduction in wound tensile strength. This may be due to the
vascular damage resulting in ischemia [10,11]. Each wound is an alarm
for health and needs instant care. Generally, wounds are of two types on
the basis of origin- external and internal. External origin wounds are
like cuts, injuries, burns and bruises. These external wounds may fre-
quently go unnoticed by diabetic patient because of peripheral neuro-
pathy. Internal origin wounds like skin ulcers and calluses cause de-
struction of skin and nearby tissues with chances of bacterial infection.
Existing standard approach employs series of medical treatments to
clean and eradicate the infected tissue, and maintain moisture with
adequate blood supply [12]. Recent studies have engaged in under-
standing the critical factors that influence healing process. Although a
great deal remains to be learned, these studies may lead to therapeutics
that will promote proper tissue repair and improve impaired wound
healing. Present review is an attempt to reveal the molecular events
responsible for delayed wound healing, molecular targets for complete
healing and recent advancements in its management.
2. Mechanistic insight
Diabetes delays the healing process leading to a non-healing wound
including various complications with associated psychiatric stress and
depression. These complications consist of functional limitations, dif-
ficulty in walking, and infection like cellulitis, abscess, osteomyelitis,
gangrene, and septicaemia. Impairment of healing in diabetic patients
is familiar but the link between patho-physiology and impaired wound
healing in diabetes is still an unknown etiology. The healing process
necessitates collaboration between inflammatory cells and biochemical
mediators stimulated by various factors. However, alteration of the
cellular and biochemical factors and activities have been implicated in
the failure of wound healing in diabetics.
Cells involved in wound healing process are neutrophils, monocyte,
macrophages, keratinocytes, fibroblasts, T cells, B cells, mast cell and
endothelial cells. These cells are actively involved in the production and
regulation of various cytokines and growth factors. Monocyte, which
later transform into macrophages is the foremost producer of pro-infl-
ammatory cytokines IL-1β2, TNF-α3, IL-64 and VEGF5, IGF-16 and TGF-
2
Interleukin-1β
3 7
Tumour necrosis factor-α
4 8
Interleukin-6
5 9
Vascular endothelial growth factor
6 10
Insulin-like growth factor-1
2
Biomedicine & Pharmacotherapy 112 (2019) 108615
β7 in both diabetic and non-diabetic conditions. Neutrophils along with
T and B cells are also a significant producer of TNF-α, IL-10 and other
cells, keratinocytes, fibroblasts, mast cells and endothelial cells. These
cells also contribute in production of VEGF, IGF-1 and TGF-β [113].
Macrophages are pivotal contributor in healing. Hyperglycaemia and
oxidative stress changes the epigenic code that results into change in
macrophage polarization and its modulation. Dys-regulated macro-
phage polarization is one of the main reasons in delayed wound healing
[13,14]. Studies revealed that in diabetes, a complex mechanism in-
volve at molecular level which is responsible for delayed wound
healing. Activities like sustained production of pro-inflammatory cy-
tokines, impaired angiogenic response and microvascular complications
[10], impaired macrophage and neutrophils function [15], impaired
keratinocytes and fibroblast migration and proliferation and impaired
production of healing-associated factors like impaired growth factor
production has been reported in diabetic animal models [16].
The phases of healing process in diabetic patients are also stalled by
other factors, including specific metabolic deficiencies, impaired phy-
siological responses like hypoxia due to glycation of haemoglobin and
alteration of red blood cells membrane and narrowing of blood vessels
[17]. Hypoxia involves decreased oxygen supply to wounds due to
narrowed blood vessels. Glycation of haemoglobin causes deficient
supply of nutrients and oxygen to tissue which further delay the healing
process. Hypoxia/glucose deficiency and deformed proteins produce a
stress response to cell by accretion of unfolded proteins within en-
doplasmic reticulum known as UPR8 . This UPR is activated just after
tissue or skin injury and linked to production of pro-inflammatory
mediators. DWs showed sustained induction of UPR along with aug-
mented expression of the pro-inflammatory chemokine as compared to
normal wounds [18].
Local ischemia due to microvascular complications in diabetes
considerably delays wound healing. miRNAs9 are a class of noncoding
RNAs of 19–24 nucleotides in length that link in numerous physiolo-
gical processes and play an important role in these complications. Al-
tered levels of miRNAs have been reported in various diseases and
impaired wound healing [19]. One of the miRNAs, MiR-210 is induced
in hypoxic situations and targets E2f3 that reduce keratinocyte pro-
liferation in wound healing [20]. MiR-200b decreases angiogenesis by
steering globin transcription factor 2 and VEGFR210 [21]. Similarly
various miRNAs like miR-130a, miR-21, miR-146a, miR-198 and miR-
Transforming growth factor-β
unfolded protein response
Micro RNA
Vascular endothelial growth factor receptor
S. Patel, et al.
26a involve in diabetic wounds that affect epithelization, delay in-
flammation, fibroblast migration, keratinocyte migration, re-
epithelialization and angiogenesis [22,23]
Along with these, there are some physiologic factors like increased
serum matrix metalloproteinase-9 [24], impaired collagen accumula-
tion and variation in the ratio of collagen types, dysregulation in the
neuropeptide expression in the skin along with a suppressed infl-
ammatory response [25], deficiency of thrombin-activatable fi-
brinolysis inhibitor [26], AGE11 modification of PDGF [27], decreased
number of epidermal nerves, epidermal barrier function [10] and
misbalance between the accumulation of ECM components and their
remodelling by matrix metalloproteinase [17,28] are responsible for
slow healing process in diabetic patients (Fig. 2).
2.1. Roles of chemokines, free radicals and oxidative stress
In last decades, noteworthy evidences have been generated to sup-
port a number of mechanisms as shown in Fig. 3 which influence dia-
betic wounds including polyol pathway, hexosamine pathway, dia-
cylglycerol pathway, nitric oxide blocking, PKC (protein kinase C)
pathways, formation of AGEs i.e. maillard reaction and intraglomerular
hypertension induced by glomerular hyperfiltration which lead to
neuropathy. These mechanisms are stimulated by mitochondrial over-
production of reactive oxygen species [29] and oxidative stress. In
diabetes, high oxidative stress plays a major role in complications and
impaired healing process. One of the transcription factor NRF212 con-
trols the adaptive response to oxidative stresses as well as decreased
apoptosis, promote cell migration, proliferation, and cell differentiation
[30]. High glucose and oxidative stress activates NRF2 to control and
repair the impairment. Long et al had shown that inducing NRF2 ac-
tivation reduced diabetes-induced oxidative stress levels, regulates the
expression MMP-9, TGF-β, migration and proliferation-related genes
via direct or indirect mechanisms [31].
ATF-313 is a stress-inducible gene, and its expression is induced B-
cell dysregulation and diabetic complications [32]. The irregular pro-
inflammatory response activates ATF-3 and iNOS and induces oxidative
stress, which might be responsible for the prolonged healing processes.
Badr et al revealed that irrationally up-regulated expression of ATF-3
and iNOS tailed by an increase in free radical levels and rise in caspase-
3,-8, and -9 activityare responsible for impaired cellular differentiation
and remodelling phase in healing process [33].
Numerous proinflammatory cytokines plays a major role in leuko-
cyte accumulation (monocytes /macrophages/ neutrophils/ immature
dendritic cells) like MIP1α14, MIP-215 and KC16 and human β-defensin
(HβD 1, 2, 3) as antibacterial in healing process. CX3CL117 is stated as a
soluble chemokine and membrane-bound form on the surface of cells
promoting macrophage and fibroblast accumulation [34–36]. Badr
et al. revealed that abnormal expression of MIP1 α, MIP-2, CX3CL1,
reduce level of HβD 1, 2 and 3, irregular activation of STAT318 and
decline in the activation of AKT/PKB (serine/threonine protein kinase
B) and NF-κB19 . All these collectively contribute tointerrupt healing in
diabetic wounds [34,37].
Diabetic peripheral neuropathy lead to sensory, motor and auto-
nomic dysfunction, each of which contributes to delayed wound
healing. In sensory neuropathy, sensation to pain either is lost or absent
creating most important threat for the growth of diabetic wounds.
11
Advanced glycation end-products
12
Nuclear factor-E2-related factor 2
13
Activating transcription factor-3
14
Macrophage inflammatory proteins 1α
15
Macrophage inflammatory proteins 2
16
Keratinocyte derived chemokines
17
Fractalkine
18
Signal transducer and activator of transcription 3
19
nuclear factor-κB
3
Biomedicine & Pharmacotherapy 112 (2019) 108615
Abnormal glycation of nerve cell proteins and the unfortunate activa-
tion of protein kinase C due to hyperglycaemia and oxidative stress lead
to nerve dysfunction and ischemia [38]. Lack of protective sensation in
diabetic wounds leads to unnoticed progression of wounds to worse.
Recently Huang et al., reported that alteration in the Akt/mTOR
pathway results in impaired wound healing in diabetes induced rat
model [39]. Similarly, Lima et al reported, Insulin induces activation of
insulin signalling pathways i.e IR/SHC/ERK and IR/IRS/PI3K/AKT
pathways in wound healing. By inducing these pathways it increases
VEGF and SDF1a tissue expression, increased eNOS phosphorylation,
angiogenesis and improved healing in diabetes [40]. Studies revealed
the role of matricellular proteins in wound healing which linked with
the proteins of the ECM and connecting them to cell surface receptors.
One of the matricellular proteins, AL-420 facilitates keratinocyte mi-
gration, reepithelialization and angiogenesis. AL-4 can connect with
integrin β1, and activate the SRC, ERK, and AKT signaling cascades and
start JAK1/STAT3 activation. Activated STAT3 can induce the up-reg-
ulation of iNOS21 expression and increase NO production from the
keratinocytes in the wound tissue and promote angiogenesis. Normally
AL-4 expression has been low in normal skin and is significantly ele-
vated upon injury. But in case of diabetic patient, AL-4 expression re-
mains low, that delayed the healing process by affecting angiogenesis
and re-epithelialization [41].
2.2. Role of immune system
Suitable co-ordination of innate immune system has an important
role in wound healing. TLRs22 are important source for the initiation of
the innate immune and inflammation response. Down regulation of
TLRs-2 in injured tissue impairs or weakens the immune system and
inflammation response [42–44] in diabetic patient which causes re-
duced chemotactic effect that delays the recruitment of various in-
flammatory cells. Diabetic patients are highly susceptible to infection
caused by delayed wound healing and immuno-suppression [42]. Bac-
terial connections on the wound are important in the etiology of dia-
betic wounds and it forms biofilms. These biofilms provide a safeguard
to microbes from antimicrobial agents and immune system and inter-
rupt the healing process. It is the most common reason of lower limb
amputation in diabetic wounds [45].
Inflammatory cells like neutrophils, monocyte, T cells, B cells and
mast cell play a chief role in the immunity. Dysegulation of these cells
may be decisive in the inhibition of diabetic host immunity. Elevated
levels of pro-inflammatory cytokines such as IL-6 and TNF-α in diabetes
causes interrupted inflammatory cascade, hyperinflammation and in-
sulin resistance. Elevated level of TNF-α may be due to accumulation of
effector T cells. Maura et al found lower naive T-cell number and a
poorer T cell receptor (TCR-Vβ) range in diabetic wound patients that
lead to the accumulation of effector T cells [46].
Immunity is also influenced by high level of AGEs inducing pro-
duction of various cytokines such as IL-6 and TNF-α. AGEs also obstruct
the collagen production, induces apoptosis, excessive immune-re-
sponses and negative regulations of the cell physiology leading to im-
paired healing [47]. Mast cells are potent releaser of angiogenic factors
like FGF, VEGF, and TGF-β1 [48]. Various studies support the role of
mast cells in wound healing as they act together with macrophages,
endothelial cells, and fibroblasts. It plays an important role in matrix
restructuring and disturbs the balance between pro-angiogenic factors
and anti-angiogenic factors in wound tissues [49]. Bevan et al revealed
that in genetically diabetic mice, there was delayed vascular regression
due to decrease in the number of mast cells and their dysfunction [50].
Nishikori et al demonstrated the role of mast cell in diabetic wound.
20
Angiopoietin-like 4
21
Inducible nitric oxide synthase
22
Toll like receptors
S. Patel, et al. Biomedicine & Pharmacotherapy 112 (2019) 108615

Fig. 2. Factors responsible for Diabetic Wounds.

Fig. 3. Major pathways responsible for decreased wound healing in diabetes [4].

They concluded impaired proliferative phase in healing process in assist endothelial cell migration, stimulate pro-collagen synthesis and
diabetes due to delayed increment of mast cells. The dysfunction of protein homeostasis [43,53]. In diabetes, level of HSPs (HSP90, HSP70,
mast cells affects the angiogenesis in proliferative phase and vascular HSP47 and HSP27) decreases along with their downstream molecules
regression in the remodelling phase [48]. Tellechea et al, revealed in his TLR4 and p38-MAPK [54] that might be responsible for impaired
experiment that mast cell degranulation was enhanced in the skin of healing process.
humans and mice with diabetes that led to impaired healing process.
Mast cell degranulation inhibitors like disodium cromoglycate, quer-
3. Role of Growth factors in impaired wound healing
cetin, and luteolin might be a potent drugs to improve wound healing in
diabetes [49]. The RNA expression of MIF (Macrophage Migration In-
Normal wound healing cascade is well coordinated and synchro-
hibitory Factor) genes deceases in diabeties, which is an important
nised by growth factors, different MMPs (Matrix metalloproteinase),
molecule in pro-inflammatory innate immune reactions. Studies re-
cytokines, inflammatory cells, keratinocytes, fibroblasts and en-
ported that decreased level of MIF in diabetic wound might be re-
dothelial cells. Growth factors are biologically active polypeptides
sponsible for impaired production of endothelial progenitor cells and
which are involved in all phase of healing process [55]. They promote
healing process [51,52].
the early inflammatory phase during the granulation phase of tissue
Heat shock proteins (HSPs) promotes wound healing by recruiting
formation. Compromised wounds frequently show defects in the type
dermal fibroblasts, stimulate cell proliferation, differentiation of kera-
and amount of growth factor due to change of their expression, de-
tinocytes, decreases oxidative stress, alleviating actin microfilaments,
creased production, decreased release, trapping and excessive

4
S. Patel, et al.
degradation [56]. Balance between matrix formation and matrix de-
gradation characterizes ECM synthesis with optimum healing. Factors
regulating ECM formation like VEGF [57], IGF-I, IGF-II [58], TGF-β23
[59], KGF24 [60], PDGF25 [61], EGF26 [62], FGF27 [63,64], TNF- α and
IL-6 are noticeably decreased in diabetic patients. Growth factors play a
critical role in initiating and sustaining the different phases of wound
healing (Fig. 4). Any alteration i.e. down-regulation of growth factor
receptors and rapid degradation of growth factor leads to delayed
wound healing in diabetics.
Platelet releases the PDGF that is a key serum mitogen and induces
fibroblast proliferation, matrix production, and maturation of con-
nective tissue [65]. PDGF is synthesized continuously in the wound
milieu by macrophages which are major cell in the late inflammatory
phase. PDGF works as a chemo-attractant for fibroblasts and in-
flammatory cells. It facilitates synthesis of glycosaminoglycans, pro-
teoglycans and collagen. It acts as a key mediator in the migration and
proliferation of fibroblasts, production of granulation tissue proteins
and provisional ECM and angiogenesis during the healing process [66].
PDGF and its receptors expression is decreased in diabetic wounds,
signifying its role in healing process [67]. Various clinical studies using
PDGF have shown enhanced healing time [68].
bFGF28 posses stimulatory effect on the growth and differentiated
function of fibroblasts and on the proliferation of vascular smooth
muscle cells, endothelial cells, extracellular matrix metabolism, growth,
and movement of mesodermally derived cells. It increases the rate and
degree of granulation tissue formation and stimulates healing process
[69].
VEGF is one of the most potent known angiogenic cytokines in the
skin, and the amount of VEGF present in a wound can notably impact
healing and supports rate-limiting steps of vasculogenesis and angio-
genesis. It mainly involves in deterioration of the extracellular matrix of
existing vessels by proteases and causes migration and proliferation of
capillary endothelial cells [70]. VEGF increases capillary density in
diabetic wounds and improves the blood perfusion and metabolism in
injured tissue. Restoration of blood flow to injured tissues facilitates
oxygen and nutrients supply to support the growth and task of re-
parative cells which promotes wound healing. It is the main regulating
factor in the revascularization and permeability of the wound site, and
participates in the formation of the granulation tissue. Roles of VEGF be
governed by activation of its receptors, first receptor VEGF receptor-1
activation leads to inflammation while activation of VEGF receptor-2
lead to angiogenesis [71]. The relatively low level of VEGF in local
wound is due to diabetes responsible for impaired wound healing. Re-
search studies found that abnormal patterns of VEGF receptors, de-
creased VEGF mRNA levels, increased VEGFR-1 level and decreased
VEGFR-2 level is main reason for non-healing status of wounds [72].
Platelet releases EGF augmenting the epidermal cell, cell motility,
cellular migration, mesenchymal regeneration, angiogenesis and cell
proliferation after binding to the EGF receptor [73]. IGF-1 and IGF-2
are peptide that forms a complex Insulin-like growth factor (IGF). IGF-1
contributes in wound healing by participating in cell granulation and
re-epithelisation, stimulating chemotaxis of endothelial cells and pro-
liferation of keratinocytes and fibroblasts. However, in diabetes pa-
tients, expression of IGF-1 is decreased which may be the reason for cell
granulation imperfection [74,75]. Its affinities are modulated by the pH
of the wound environment [16].
The decreased levels of IGF-1 and TGF-β at the wound tissue were
reported in both diabetic animals and human responsible for delayed
23
Transforming growth factor β
24
Keratinocyte growth factor
25
Platelet derived growth factor
26
Epidermal growth factor
27
Fibroblast growth factor
28
Basic fibroblast growth factor
5
Biomedicine & Pharmacotherapy 112 (2019) 108615
wound healing process [76]. TGF-β recruits and promotes stimulation
of inflammatory cells neutrophils, macrophages, lymphocytes, kerati-
nocytes, fibroblasts and production of growth factors. These accelerate
vascularisation, angiogenesis, and formation of ECM and hindered de-
gradation of ECM [77]. The reduced concentration of TGF-β has been
reported in wound healing in diabetic case [59]. Various studies de-
monstrated that MMP-encoding genes have a TGF-β1-dependent in-
hibitory element in the promoter region, which down-regulate the
gene’s expression. Decreased levels of TGF-β and increased expression
of MMPs causes excessive degradation of the growth factors [78]. Along
with MMP-encoding genes, Transcription factors like Smad-2, Smad-3
and Smad-4 also activate and repress TGF-β target genes. TGF-β1 ac-
tivates the Smad-2 and 3 for production of collagen [79]. Decrease in
level of TGF-β1 lead to increased recruitment of activated inflammatory
cells causing delayed inflammatory phase to proliferation phase of
healing process in DWs. High level of TGF-β3 was thought to be the
reason for decreased level of TGF-β1 in diabetics [80] which lead to
increased macrophage activity and decreased collagen synthesis. In
diabetics, high glucose level augmented macrophage activity producing
more reactive oxygen species leading to prolonged inflammatory phase
[81]. Decreased level and expression of these growth factors lead to
poor and prolonged wound healing process in diabetes.
4. Role of MMPs in impaired wound healing
Matrix metalloproteinase is a family of 26 zin. dependent en-
dopeptidases that play crucial role in initial wound debridement, as
well as in the phases of angiogenesis, epithelialization, and remodelling
of extra cellular matrix [82]. Every matrix proteins like collagens,
basement membrane collagens, proteoglycans, elastin, fibronectin are
digested by MMPs. The gelatinase (MMP-2 and MMP-9) are two pro-
teinases primarily responsible for breaking down of type IV collagen
from the basic matrix. These are present as inactive zymogens that need
removal of the pro domain for their activation. Activity of MMPs is
regulated by complexation with TIMPs29, which block contact to the
active site. Balance between MMPs and TIMPs is required for a proper
wound healing as supported by number of studies [83]. MMPs are in-
volved in various stages of wound healing like cell migration by pro-
teolysis of the ECM, in re-epithelialization by degradation of junctional
proteins, in leukocyte invasion by creating a chemotactic gradient, in
inflammation by processing of multiple cytokine either by inhibition or
by activation [84]. In these enzymes MMP-1 is crucial for wound re-
epithelialization, MMP-2 is significant during angiogenesis and pro-
longed matrix remodelling and MMP-3 is vital for normal wound con-
traction and in remodelling the basement membrane. While role of
MMP-9 during healing is indistinct; it may be involved in separating
keratinocyte from the basement membrane before migration and be
used to assist matrix degradation by neutrophils and macrophages for
the period of elimination of necrotic or damaged tissue [85]. Studies
revealed that high levels of metalloproteases are a feature of diabetic
wounds, and the MMP levels in chronic wound fluid are almost 60 times
higher than acute wounds. This increased protease activity supports
tissue destruction and inhibits normal repair processes [86]. One of the
possible reasons behind this is high glucose concentrations that directly
alter the level and expression of MMPs, decrease the expression of
TIMPs via effects of persistently high levels of pro-inflammatory and
pro-fibrotic cytokines due to increased activation and invasion of in-
flammatory cells, and indirectly affect MMPs by formation of advance
glycation products [68]. These consequently abolish growth factors,
receptors, and matrix proteins crucial for wound healing.
29
Tissue inhibitors of matrix metalloproteinase
S. Patel, et al.
Fig. 4. Role of major Growth Factors on different cells and process involved in wound healing.
5. Molecular targets
Increased understanding of diabetes and its role in impaired wound
healing at molecular level have broadened the wound research over
recent years. These studies revealed that impaired wound healing in
diabetics is due to unusual cellular expression of all participating cells
and dys-regulation in the expression of cytokines, growth factors and
various other molecular factors required for coordinating the normal
healing process. As a result, chronic non-healing wounds are unable to
step forward in synchrony and are checked mainly in the inflammatory
phase. Numerous molecular factors/targets for management of diabetic
wounds have been identified over the years. These management ap-
proaches are categorized on the basis of molecular targets which di-
rectly or indirectly modulates their activity.
The targets, which directly interact, include various growth factors
(PDGF, TGF-α, EGF, VEGF, FGF, and KGF), autologous keratinocytes or
autologous fibroblasts and stem cells. The role and importance of these
targets were discussed in previous sections. Various agents might in-
directly affect the molecular targets by up-regulated or down-regulated
expression of growth factor, pro and anti inflammatory cytokines,
MMP, nitrous oxide level, collagen synthesis /degradation and factors
promoting angiogenesis depending on the specific target. These wound
management approaches are classified on the basis of types of ther-
apeutic agents used as drugs, growth factor, other approaches and stem
cells and highlights of available clinical status for treatment of diabetic
wounds are shown in Table 1. Table 1 also shown the molecular targets
directly or indirectly involve in therapeutic approaches by formations
or system or drug.
5.1. Natural product based treatment
Traditionally natural source obtained from different sources have
been of prime importance to heal wound like turmeric, castor leaves,
neem bark, rosemary, ginseng and many more. It has been reported that
70% of commercialized products contains plant based active in-
gredients, rest 20% are of mineral base and 10% are of animal based
and more than 13,000 have been worked out particular to accelerate
the process of wound healing. Plant actives which are involved in
healing process include glycosides, steroids, saponins, resins, mucilage
and flavonoids. Table 2 enlists most of the medicinally active plants
which were demonstrated for their wound healing activity in diabetes
and Table 3 depict the available marketed products used in manage-
ment of diabetic wounds.
6. Clinical trials
Various clinical trials were on going to uncover a novel treatment
approach for this worldwide health ailment. Tardivoe et al., 2014
6
Biomedicine & Pharmacotherapy 112 (2019) 108615
performed a clinical trial using photodynamic therapy and result shown
that rate of amputation in the photodynamic therapy group was 0.029
times the rate in the control group [87]. Park et al., 2018 performed a
phase III multicenter, double-blind, randomized, placebo controlled
trial to evaluate the efficacy and safety of a novel spray-applied growth
factor therapy containing recombinant human epidermal growth factor
(rhEGF) for the treatment of diabetic wounds. This group concluded
that patients in the rhEGF treated group notably completed healing as
compared to placebo group (73.2% vs 50.6%, respectively; p = 0.001).
Also, healing velocity was found to be faster in the rhEGF treated group
(p = 0.029) in spite of HbA1c levels. The rhEGF treated group had a
shorter median time to 50% ulcer size reduction and shorter time to
complete ulcer healing as compared to placebo group [54]. Asadi et al.,
2017 performed a randomized, single-blind, placebo-controlled trial
using low-intensity cathodal direct current. Results of this study sug-
gested that on applying electric stimulation to ischemic ulcers have
positive effects and promote healing by stimulate the release of HIF-1α
and VEGF in the wound area [88]. Soleimani et al., 2017 performed a
randomized, double-blind, placebo-controlled trial using flaxseed oil
omega-3 fatty acids. This group concluded that on supplementation of
omega-3 fatty acids for 12 weeks among diabetic wound patients had a
favorable effects on parameters of ulcer size, indicators of insulin me-
tabolism, plasma TAC, serum hs-CRP, and GSH levels [89]. Similar
various clinical trials have been performed in recent years to promote
healing in diabetic wound patients was described in Table 4.
7. Future therapeutic strategies
Diabetic wounds consequences from numerous risk factors in-
cluding peripheral neuropathy, peripheral artery disease and foot ail-
ments. In spite of the development in technologies such as bioengi-
neered skin cells and the prevalent application of standard care in
treating diabetic wounds, it has been reported that the occurrence of
wound healing has remained at less than 50%. The research on diabetic
wounds is proceeding hastily evident by new therapeutic approaches
other than conventional such as single growth factor, dual growth
factor, skin substitutes, cytokine stimulators, cytokine inhibitors, matrix
metalloproteinase inhibitors, gene and stem cell therapy, extracellular
matrix and angiogenesis stimulators. Future treatment approaches are
at present under analysis for the treatment of diabetic wounds includes
recombinant growth factors, platelet-rich plasma, Sphingosine 1-phos-
phate, Substance P, stem cell therapy, MMP inhibitors, shock-wave
therapy, laser therapy and natural product based treatment. These ap-
proaches are the crucial need for a more realistic, secure and efficient
therapy for diabetic wounds (Tables 1 and 2). The majority of these
approaches are currently under investigation and their use has mostly
been restricted to clinical trials.
 Table 1
Therapeutic strategies explored management of wounds in diabetics.
Therapeutic agents Delivery System and Route Molecular Target Outcome and Mechanism Target tissue/ animal Reference
S. Patel, et al.

model

Growth factors
PDGF/TGF-α Topically/ Gel PDGF and TGF-α Promoting healing by increasing keratinocyte and fibroblast Genetically diabetic [58]
mitogen mouse
basic fibroblast growth factor PELA Nanofibres/ Topically Fibroblast Enhanced proliferation, migration, fibroblast adhesion, re- Diabetic rats [90]
epithelization, angiogenesis, ECM restoration and remodelling
Human epidermal growth factor Cream EGF Reduces the healing time Diabetic foot ulcers [91]
Recombinant epidermal growth factor PLGA Microspheres rhEGF Increased healing by inducing fibroblasts proliferation and Diabetic ulcers [92]
enhancing proliferating cell nuclear antigen in the epidermis
PDGF Gel PDGF Increased angiogenesis, cell proliferation and epithelialization Diabetic rats [67]
basic fibroblast growth factor collagen/gelatin sponge ——— Improve healing Chronic skin ulcers [93]
Platelet Hyaluronic acid Gel PGDF, TGF-α, VEGF Enhance granulation tissue formation, re-epithelization and Cutaneous chronic [56]
reduce pain wounds
Recombinant PDGF Gel PDGF Increases reepithelialization, granulation tissue thickness, Diabetic rats [94]
capillary density and improved healing by increased c-fos protein
expression and ERK phosphorylation
Fusion protein (CBD-VEGF) Collagen Domain VEGF Increases vascularisation and maintain VEGF activity Diabetic rat model [95]
Recombinant human acidic fibroblast Chitosan crosslinked collagen sponge FGF Increases angiogenesis, collagen generation and dermal cell Diabetic rats [96]
growth factor proliferation
Recombinant epidermal growth factor Poly-epsilon-caprolactone and poly- EGF Promotes proliferation and expression of keratinocytes Diabetic ulcers [97]
ethyleneglycol Nanofibres
Arginine and Epidermal growth factor Hyaluronic acid sponge EGF Decreased wound size by increasing the epithelization [98]
bFGF Collagen-gelatin sponge FGF Accelerate ECM formation and angiogenesis Diabetic mouse model [99]
Keratinocytes growth factor Chimeric Nanoparticles KGF Increased healing by enhancing reepithelialization and Chronic wounds [100]
granulation tissue formation

7
plasmid bFGF Poly(Ethylene Imine) electrospun Fibers FGF Increased healing by enhanced collagen synthesis, maturation Diabetic skin wound [101]
and reepithelialization
rhEGF Dextrin conjugated Topically ——— Accelerated wound closure, neo-dermal tissue formation, (Db/db) diabetic [73]
increased granulation tissue deposition and angiogenesis mouse
Dual growth factor Poly(lactic-co-glycolic acid) nanoparticles in VEGF, PDGF-BB Accelerated the healing process by increasing angiogenesis, re- ——— [102]
chitosan nanofiber system epithelialization and granulation tissue formation
PDGF Collagen Chitosan hydrogel/ Topically ——— Increased collagen biosynthesis and by reducing reactive oxygen Cutaneous wound [103]
species healing
PDGF-BB Carboxymethyl cellulose Hydrogel/ Topically ——— Accelerated healing by enhanced granulation tissue formation Genetically diabetic [104]
and angiogenesis mice
bFGF Chitosan film/ Topically FGF Reduced wound area and promoted healing by increasing ECM Genetically diabetic [105]
formation mice
Recombinant human Epidermal Polyurethane foam/ Topically ——— Accelerated healing by increasing contraction rate, re- Diabetic wounds [106]
growth factor epithelialization and collagen deposition
VEGF Poly(lactic-co-glycolic acid) nanoparticle VEGF Receptor -2 Enhanced proliferation and migration of keratinocytes and Non-diabetic and [107]
upregulated the expression of VEGFR2 at mRNA level diabetic wounds
Synthetic drugs
Pravastatin Subcutaneous sponges eNOS expression Improve wound breaking strengths, hydroxyproline accumulation Diabetic wound [108]
by up-regulation of eNOS and NO expression
Azelnidipine Solution/Orally eNOS Accelerated healing by stimulating NO production and enhancing Skin Wound in [109]
histologic processes Diabetic Rats
AL–CS–PGA hydrogel Hydrogel Collagen Increases healing by collagen regeneration and epithelialization Diabetic rats [110]
Atorvastatin gel Carbopol Hydrogel ——— Increased healing with closure and epithelisation within 7 days Diabetic rats [111]
Erythropoietin Cream VEGF Decreased wound closure time, increased VEGF and Diabetic rats [112]
hydroxyproline and microvascular density
Pentoxifylline Cream MMPs and TIMP-1 Accelerates healing by decreasing MMPs expression and increased Diabetic rats [113]
TIMP-1 expression
(continued on next page)
Biomedicine & Pharmacotherapy 112 (2019) 108615
 Table 1 (continued)

Therapeutic agents Delivery System and Route Molecular Target Outcome and Mechanism Target tissue/ animal Reference
S. Patel, et al.

model

Deferoxamine Intra-peritoneally HIF-1α, SDF-1α, VEGF Increased neovascularisation and healing by promoting Diabetic rats [114]
endothelial tube formation and cell proliferation through up-
regulation of HIF-1α
Topically ——— Increased neovascularisation and healing by decreasing mRNA Diabetic rats [115]
expression and protein levels of TNF-α, MMP-9 and IL-1β
Substance P I.V. endothelial cell adhesion molecules or Increases early leukocyte and macrophage density in healing and Diabetic murine [116]
IL-8 promoting cutaneous wound repair wounds
Topical application ——— Decreased levels of TNF-α, IL-1β and MMP-9 and increase IL-10 Diabetic rat [117]
levels and increased the expressions of VEGF, TGF-b, SDF-1α, HO-
1 and e-NOS.
Reverses the proinflammatory state in diabetic wound and Diabetic skin wounds [118]
modulate activation of macrophage and improve healing
Propranolol Solution Orally VEGF, TGF-β, IL-8, MMP-9 Reduces inflammatory cell and MMP-9 levels and increases cell Diabetic rats [119]
proliferation, mast cell number, collagen deposition, blood vessel
density, and nitric oxide level
Glucophage (metformin) nanofibrous collagen/PLGA membrane MMP-9 Faster healing by increased re-epithelialization and collagen I Diabetic wound [120]
synthesis by down-regulating MMP-9
Novel nano-insulin Silver nanoparticles Coated with Insulin IL-6, TNF-α, IL-10 Regulation of balance among IL-6, TNF-α and IL-10 at the wound Diabetic rats [121]
site to promote faster wound remodeling
GW501516 Polymer Microparticle/ peroxisome proliferator-activated Reduced the oxidative wound micro-environment to accelerate Diabetic wound [122]
receptor healing
MK0626 Dipeptidyl peptidase-4 inhibitor/ Oral HIF-1α / SDF-1 Significantly improved healing, angiogenesis, and endogenous Diabetic mice [123]
progenitor cell recruitment.
Poly (caprolactone) /gelatin Conducive Poly (caprolactone) /gelatin Epithelial-to-mesenchymal transition Improve diabetic wound healing by releasing Si ions and ano- Diabetic mice [124]
nanofibrous composite scaffold nanofibrous composite scaffold containing and endothelial mesenchymal fibrous structure

8
silicate-based bioceramic particles transformation pathway
Adenine Ointment AMP-activated protein Kinase, PPARδ Increasing the healing by increasing angiogenic related protein Diabetic mice [125]
PPARδ and decrease the AGE receptors.
Bee venom Subcutaneous injection Nrf2, Ang-1 and Tie-2 signaling Enhanced wound by rising collagen and BD-2 expression and Diabetic mice [126]
reinstate the levels of Ang-1 and Nrf2 and Tie-2 downstream
signaling
Curcumin Composite graft with Cytomodulin coupled —— Better and faster wound healing with regenerating a skin of Diabetic rats [127]
porous PLGA microparticles higher tensile strength.
Other approaches
Sphingosine 1-phosphate Subcutaneous EDGs Accelerates healing by increased vascular formation within the Diabetic mice [128]
granulation tissue
Adiponectin TGF-β Restrain proliferation and differentiation of keratinocytes, and Diabetic wound [129]
regulates the expression of TGF-β
Neurotensin 5-methyl pyrrolidinone Chitosan Dressing TNF-α, IL- 1β, collagen expression Reduced inflammatory status, improve healing, re- Diabetic wound [130,131]
epithelialization by decreasing inflammatory infiltrate and
increasing fibroblast migration and collagen deposition
Collagen dressings TNF-α, IL-1β Reduced inflammatory cytokine TNF-α, IL-1β and MMPs, Diabetic mice
increased fibroblasts migration and collagen expression and
deposition
Broad-spectrum MMP inhibitor Sepharose resin, Topically MMP and TIMP Accelerate healing, re-epithelialization and inhibit MMP-9 Diabetic wound [28]
activity
Hyaluronic acid Solution, I.P. TGF-β Improved healing by increasing skin remodelling proteins, TGF-β Genetically diabetic [132]
and transglutaminase-II mice
HoxD3 plasmid DNA Methylcellulose Film HoxD3, Col1A1 and β3-integrin Significant acceleration of wound closure by increasing mRNA Diabetic mice [133]
expression of HoxD3, Col1A1 and β3-integrin leading to
enhanced angiogenesis and collagen deposition
Human Amniotic fluid Proteome ——— ——— Accelerates healing by activating mitosis and angiogenesis Diabetes-impaired [134]
wound
(continued on next page)
Biomedicine & Pharmacotherapy 112 (2019) 108615
 Table 1 (continued)

Therapeutic agents Delivery System and Route Molecular Target Outcome and Mechanism Target tissue/ animal Reference
S. Patel, et al.

model

Angiopoietin-like 4 Topical Nitric Oxide Increases diabetes induce wound healing via increasing nitric Diabetic mice and [41]
oxide production accelerated reepithelialization and improving human skin tissue
angiogenesis
Stem cells
Adipose tissue-derived Mesenchymal Intra-dermally VEGF, HGF Enhances healing by anti-inflammatory and anti-apoptotic effects Diabetic rats [135]
Stem Cells
Autologous Keratinocytes or Cell suspension Fibroblast, Keratinocyte Accelerate healing by enhancing re-epithelialization rate Diabetic porcine [136]
Autologous Fibroblasts wound
Allogenous skin fibroblasts Cell suspension Fibroblast Promote healing by increasing re-epithelialization, fibroblasts Diabetic sheep [137]
and angiogenesis
BM derived Mesenchymal Stem Cells Subcutaneously Cell suspension ——— Stimulate healing by increasing production of cytokines and/or Murine and human [138]
by stimulation of endogenous resident cells cutaneous wounds
EGF, VEGF, Prolyl4-hydroxylase, Ki-67 Enhances healing by reduction in topical pro-inflammatory Diabetic rats [139]
expression reaction and increases VEGF
Mesenchymal Stem cells ————— ————— Promotes healing by enhancing angiogenesis Diabetic wound [140]
Electrospun Collagen Scaffold Fibroblast Enhancing healing by promoting fibroblast migration and Diabetic mice [141]
proliferation
Topical embryonic stem cells Topical injection EGF, VEGF Accelerated healing by stimulating epidermal regeneration, Diabetic rats [142]
granulation tissue formation and angiogenesis via increasing EGF,
VEGF and fibronectin
Amniotic Mesenchymal Stem Cells Injection angiogenic factors Promotes healing by up-regulation of angiogenic factors, IGF-1, Diabetic NOD/SCID [143]
EGF and IL-8 and enhanced engraftment/ differentiation mice
capabilities
Placenta mesenchymal stem cell Intradermal injection Pro-angiogenic molecules Accelerates healing by stimulating vascular regeneration Diabetic Goto- [144]
Kakizaki rats

9
BM-derived SPCs Topical ————— Improves healing via indirect mechanisms that enhanced Diabetic mice [145]
angiogenesis
Adipose tissue-derived stromal cells Atelocollagen matrix ————— Accelerating healing by increasing granulation tissue formation, Db/db mice [146]
epithelium, and capillaries
Dermal sheath derived Mesenchymal ——— IL-6, IL -8 and growth-related oncogene Enhanced keratinocytes, fibroblasts proliferation and endothelial Diabetic wound [147]
Stromal cells cells in vitro and decreases healing time
Umbilical cord blood-derived 3D fibrin gel with CD34+-derived endothelial IL-17, IL-10, ERK1/2 patway Reduces the inflammatory reaction and enhances Diabetic mice [148]
hematopoietic stem cells cells neovascularization
(CD34+cells)
Adipose-derived stem cells Injectable hydrogel system CD11b, TNF α, IL-1 Accelerated healing by inhibiting inflammation and promoting Humanized excisional [149]
angiogenesis and re-epithelialization. wound model
Adipose-derived stem cells, Injection —— Increase in the % of wound closure rates in cell-based treatments. Diabetic swine [150]
Endothelial-differentiated stem
cells
Human umbilical cord blood–derived Transplantation Collagen and (TGF)-β Improved the healing by increasing collagen synthesis and Diabetic Mice [151]
mesenchymal stromal cells angiogenesis.
Biomedicine & Pharmacotherapy 112 (2019) 108615
S. Patel, et al. Biomedicine & Pharmacotherapy 112 (2019) 108615

Table 2
Natural product based treatment for diabetic wounds.
Natural products Outcome with possible mechanism Animal model Ref.

Rosmarinus officinalis L. Reduced inflammation, debridement, increased contraction, epidermal regeneration and alloxan induced-diabetic mice [152]
Family: Lamiaceae organization
Curculigo orchioides G. Improve healing by increasing superoxide dismutase, nitric oxide and decreased lipid Streptozotocin induced diabetic [153]
Family: Hypoxidaceae peroxidation mice
Melilotus officinalis (L.) Pall. Induces micro-vascularisation and Anti-inflammatory activity Diabetic patients [154]
Family: Fabaceae
Rehmanniae Libosch. ex Fisch. & C.A. Improved healing by enhancing tissue regeneration, angiogenesis and inflammation Streptozotocin-induced diabetic [155]
Mey. control rat
Family: Orobanchaceae
Curcumin Curcuma longa L. Increased wound closure rate by reduced inflammatory induction and antioxidant activity Streptozotocin induced diabetic [156]
mice model
Family: Zingiberaceae Improved healing by increasing granulation tissue, fibroblasts proliferation and collagen Streptozotocin induced diabetic [157]
deposition rats
Enhanced healing by accelerated neovasculogenesis, increased expressions of VEGF, TGF- Streptozotocin induced diabetic [158]
β, hypoxia-inducible growth factor-1α, stromal cell-derived growth factor-1α, and heme rats
oxygenase-1
Martynia annua L. Enhanced healing by free-radical scavenging activity of the flavonoids and luteolin Streptozotocin induced diabetic [159]
Family: Martyniaceae rats
Genistein Improved healing and angiogenesis by suppression of FoxO1, iNOS activity and oxidative STZ-induced type 1 diabetic mice [160]
Genista tinctoria stress
L.
Family: Fabaceae
Lithospermun erythrorhison Siebold & Decreased vascular permeability, increased granulation tissue formation Diabetic mice [161]
Zucc.
Family: Boraginaceae
Astragalus membranaceus (Fisch.) Increased healing and post-ischemic neovascularization by augmenting blood vessel STZ induced rat with hindlimb [162]
Family: Fabaceae, density, VEGF and eNOS expression, and attenuate oxidative stress ischemia model
Rehmannia glutinosa (Gaertn.) Steud.
Family: Orobanchaceae
Astragalus membranaceus (Fisch.) Enhanced healing by increased tissue regeneration, promoting angiogenesis and Streptozotocin-induced diabetic [163]
Family: Fabaceae, inhibiting inflammation rat
Rehmanniae Libosch. ex Fisch. & C.A.
Mey.
Family: Orobanchaceae
Annona squamosa L. Enhanced epithelialization rate, cellular proliferation and collagen synthesis Streptozotocin-induced diabetic [164]
Family: Annonaceae rat
Nicotine Accelerated healing and angiogenesis Streptozotocin induced diabetic [165]
Nicotiana tabacum L. mice
Family: Solanaceae
Allium sativum L. Improve healing in diabetes Alloxan induced diabetic rats [166]
Family: Amaryllidaceae
Naringin Enhanced healing by inducing angiogenesis and down-regulate the expression of TNF-α, Streptozotocin-induced diabetic [167]
IL-1β and IL-6 and upregulate the expression of IFG-1, VEGF and TGF-b rat
Aloe vera (L.) Burm.f. Accelerated healing Streptozotocin-induced diabetic [168]
Family: Asphodelaceae rat
Sparassis crispa (Wulfen) Fr. Improve healing by promoting migration of macrophages, fibroblasts, and synthesis of streptozotocin induced diabetic [169]
Family: Sparassidaceae type I collagen. rats
Honey Promotes epithelisation Human patients [170]
Apis mellifera L.
Family: Apidae
Honey with hydroalginate Improve wound healing Human patients [171]
Astragulus polysaccharide-loaded Accelerated healing by restoration of microcirculation and promoted angiogenesis Streptozotocin-induced diabetic rat [172]
fibrous mats
Angelica sinensis (Oliv.) Diels, Improve healing by reduced neutrophil infiltration and macrophage accumulation, Streptozotocin-induced diabetic [173]
Family: Apiaceae enhanced angiogenesis, and increased collagen deposition rat
Astragalus membranaceus (Fisch.)
Family: Fabaceae,
Angelica dahurica Fisch.ex Hoffm.,
Family: Apiaceae and Gleditsia sinensis
Lam.
Family: Fabaceae
Bee venom Enhanced wound closure by increasing collagen production and reinstating the levels of Type I diabetic mouse model [33]
inflammatory cytokines by acting on ATF-3 and iNOS
Camel milk Peptide Restore the normal redox status and activate the inflammatory cascade and stimulates Streptozotocin-induced diabetic [52]
healing rat
Whey Protein Improves healing by increased glutathione synthesis and cellular antioxidant defence Streptozotocin-induced diabetic [37]
mice
Improved healing by Up-regulation of Hsp72 and keratin16 Streptozotocin-induced diabetic [174]
rat
Enhanced collagen deposition, restored the activation of STAT3, Akt and NF-κB Streptozotocin-induced diabetic [175]
mice
Propolis Enhance healing by increasing collagen production via TGF β1 and smad2, 3 signaling Streptozotocin-induced diabetic [79]
mice

10
S. Patel, et al. Biomedicine & Pharmacotherapy 112 (2019) 108615

Table 3
Marketed Products for rapid wound healing in diabetes.
Product Composed of company

Apligraf (Graftskin) Bovine collagen and living fibroblasts and keratinocytes Novartis, Switzerland
Dermagraft Cryopreserved human fibroblasts-derived dermal substitute Shireplc, USA
Becaplermin (Regranex) Platelet Derived Growth Factor-BB Smith & Nephew, Inc., USA
Bilayered living human skin equivalent Cultured keratinocytes on the fibroblast-populated collagen lattice
Angipars Melilotus officinalis Endocrinology and Metabolism Research Institute, Iran
Ampucare Azadirachta indica and Curcuma longa Venus Remedies Ltd., India
Fiblast Spray (Trafermin) Recombinant bovine bFGF Kaken Pharmaceutical Co.,Ltd.
MediHoney 80% active Leptospermum honey with colloidal alginate Derma Sciences, Inc., USA
rHuHSP90a-115 Topical protein drug
Woulgan® biogel (in clinical trial) Biotec Pharmacon’s soluble yeast beta-glucan (SBG) Biotec Pharmacon, Norway

Table 4
List of clinical trials studies on diabetic wound.
S. No. Study design Drugs/ Methods Result References

1. Randomized phase III Clinical Topical betulin gel Accelerates re-epithelialization of partial thickness wounds [176]
Trials
2. Randomized Clinical Trials Honey dressing In treated group, microbial clearance, and healing area were notably higher than control [177]
groups.
3. Randomized Clinical Trials Royal Jelly Healing area, healing rate and time not showing any change with placebo treated group. [178]
4. Randomized Clinical Trials Manuka Healing time of treated group was considerably lower than control group. And % of [179]
honey-impregnated dressing ulcers healed did not change significantly between groups
5. Randomized, Dragon's blood cream Dragon's blood cream significantly improves healing duration. [180]
Double-blind
6. Single-blinded randomized Extracorporeal Shock wave Noteworthy decrease in wound size and median time requisite for ulcer healing. [181]
controlled therapy
7. Single-arm clinical trial Autologous platelet-rich Wound area significantly decreased in treated group as compared to control. [182]
plasma gel
8. Randomized Controlled trial LeucoPatch system LeucoPatch treated group, 34% ulcers healed within 20 weeks as compared to 22% [183]
ulcers in the standard care group.
9. Randomized Controlled trial Negative pressure wound Reduces the granulation time of by 40% in diabetic wounds as compared to standard [184]
therapy wound dressing.

8. Conclusion UGC-BSR-7-341-2011 for JRF; UGC-MRP-41-748-2012 and DHR-ICMR

There has been exponential growth of research in the field of dia-
betic wound management over the past years. Impaired wound healing
is common impediment of diabetes that has potentially devastating
consequences on suffering patients. Numerous factors contribute to
impaired healing in diabetes as suggested by various researches.
Significant developments have been made on various new therapeutic
approaches and products in management of wound healing in diabetes.
Approaches involving the growth factor, dual growth factors, various
cytokines modulators, anti-inflammatory drugs, MMP inhibitors, an-
giogenesis stimulator, ECM stimulators, stem cells, and various natural
based products have been evaluated with limited achievement. Recent
studies based on combinational approach have overpowered conven-
tional approaches. It presents a hope for the researchers to go through
the new advancement in the designing of novel carrier along with un-
derstanding basic approach. Combination approaches can be an im-
portant area for future research in management of compromised
wounds. Thus, contributing towards accelerated healing of diabetic
wounds. Strong research is needed to recognize different agents that
could act at different phase of wound healing in diabetes. Getting better
clinical methodologies and system can be of assistance in recognizing
the extent of healing.
Declaration of interest
The authors report no declarations of interest.
Acknowledgements
The authors are thankful to Director, University Institute of
Pharmacy, Pt. Ravishankar Shukla University Raipur, Chhattisgarh,
no. G.30011/4/2014-HR-2016 for financial support,
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